1. FIELD OF THE INVENTION
The present invention relates to crystals of phenylalanine derivatives which have a specific structural formula, production method thereof and use thereof, and particularly the use thereof as an active ingredient of pharmaceutical compositions.
2. DISCUSSION OF THE BACKGROUND
It is already known that phenylalanine derivatives have α4 integrin inhibiting action and they are useful compounds as therapeutic agents for inflammatory bowel diseases or the like (Patent Literatures 1 and 2).
In response, the inventors have found that specific novel phenylalanine derivatives which are not specifically described in the above patent literatures have particularly high α4 integrin inhibiting activity under the existence of serum; the total clearance thereof is low; the area under the plasma concentration-time curve and bioavailability thereof are high in oral administration; and α4 integrin inhibiting activity thereof in vivo is also high in oral administration. The PCT application was filed (PCT/JP2004/019704) based on these findings.
A compound of the following formula (I) (hereinafter also referred to as a compound (I)) disclosed in Example 151 of the above PCT application or pharmaceutically acceptable salts thereof is a prodrug of a compound of the following formula (II) disclosed in Example 99 of the PCT application. The compound of the formula (II) which is the active compound has extremely excellent α4 integrin inhibiting activity, and the total clearance thereof is low (which means that it is excellent in retention in plasma). Thus, it is the compound valuable in the actual use. However, the compound of the following formula (I) disclosed in Example 151 of the PCT application is obtained by the method comprising the steps of: stirring a mixture of a corresponding carboxylic acid, corresponding alcohol and a 4M hydrogen chloride dioxane solution at 90° C. for several hours; removing the solvent and purifying the obtained crude material with high-performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA); and then collecting the compound by freeze-drying (which is the method in accordance with Method C of Examples 101 to 121 or Process 3 of Example 53). Namely, the obtained compound was an inferior crystalline form of trifluoroacetate salt.
In general, when preserving a drug substance, or manufacturing or preserving a preparation, drug substances inferior in crystallinity such as amorphia and noncrystalline solid substances are physically and chemically unstable against environmental conditions such as temperature, humidity and air, and they are highly hygroscopic. Therefore, such drug substances tend to have problems upon developing pharmaceutical compositions wherein the high purity of the substance is required, and they also tend to be accompanied by difficulties upon manufacturing on the industrial scale.
Further, in general, since drug substances inferior in crystallinity such as amorphia and noncrystalline solid substances have the degradability by moisture absorption, solvents which can be used upon manufacturing a preparation are limited to anhydrides, and, therefore, it may cause the increase in preparation cost.    Patent Literature 1: WO 02/16329    Patent Literature 2: WO03/070709    Patent Literature 3: WO2004/074264